JPS5931787A - 1,3,2-oxaazaphosphorinane-2-oxide derivative - Google Patents

Abstract

NEW MATERIAL:The 1,3,2-oxaazaphosphorinane-2-oxide derivative of formula I [R<1> is (lower alkyl, lower alkoxy or halogen-substituted) phenyl, (lower alkoxy- substituted) phenyl (lower alkyl), cyclo (lower alkyl), (halogen-substituted) lower alkyl, lower alkenyl, furyl (lower alkyl) or thienyl (lower alkyl); R<2> is halogen or NHCH2CH2X (X is halogen)]. EXAMPLE:2-Chloro-3-phenyl-1,3,2-oxaazaphosphorinane-2-oxide. USE:Synthetic intermediate of a carcinostatic agent (the compound of formula II). PROCESS:The compound of formula I wherein R<2> is halogen can be prepared e.g. by reacting the compound of formula III with the compound of formula IV. The resultant compound can be converted to another compound of formula I wherein R<2> is NHCH2CH2X by reacting with 2-halogenoethylamine (salt) of formula H2NCH2CH2X.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel 1.3.2-oxaazaphosphorinane-
This invention relates to 2-oxide derivatives.

The 1.3.2-oxaazaphosphorinane-2-oxide derivative of the present invention is represented by the following general formula [1].

In formula C, R1 is a phenyl group which may have 1 to 3 groups selected from lower alkyl groups, lower alkoxy groups and halogen atoms as substituents on the phenyl ring, and 1 lower alkoxy group on the phenyl ring. Indicates a phenyl lower alkyl group that may have ~3 atoms, a cyclo lower alkyl group, a lower alkyl group that may have three halogen atoms, a lower alkenyl group, a furyl lower alkyl group, or a chenyl lower alkyl group.

R2 is a halogen atom or NHCH2CH2X (x is ha [
Indicates a cogen atom) group. However, when R2 is a halogen atom, R1 has one lower alkoxy group on the phenyl ring.
It must not be an α-phenyl lower alkyl group, which may have up to 3 α-phenyl lower alkyl groups. ] Specific examples of each group defined by R1 and R2 in the above general formula are illustrated below.

Examples of phenyl groups that may have 1 to 3 groups selected from lower alkyl groups, lower alkyl groups, and halogen atoms as substituents on the phenyl ring include phenyl, 2
-93- or 4-chlorophenyl, 2-. 3- or 4-full 3-loff engineering, 2-. 3- or 4-bromphenyl, 2-93- or 4-iodophenyl, 3.5-dichlorophenyl, 2.6-dichlorophenyl, 3.4-dichlorophenyl, 3.4-difluorophenyl, 3.5-dibromphenyl , 2-, 3- or 4-methylphenyl, 2-33- or 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2-, 3 - or 4-methoxyphenyl,
2-93- or 4-engineered 1-xyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 3
゜4-Dimethoxyphenyl, 3,4-jethoxyphenyl, 2.5-dimethoxyphenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2-
Methoxy-3-chlorophenyl, 3.4.5-trimethoxyphenyl, 3.4.5-trimethylphenyl, 3,
Examples include 4,5-trichlorophenyl group.

Examples of phenyl lower alkyl groups that may have 1 to 3 lower alkoxy groups on the phenyl ring include benzyl, 2
-Phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylethyl, 1,1-dimethyl-2
-Phenylethyl, 5-phenylbentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-
or 3-methoxybenzyl, 2-(4-methoxyphenyl)ethyl, 2-ethoxybenzyl, 1-(3-ethoxyphenyl)ethyl, 3-(4-ethoxyphenyl)propyl, 6-(4-isopropoxyphenyl) hexyl, 4-(4-hexyloxyphenyl)butyl, 1
．． 1-dimethyl-2-(3,4-dimethoxyphenyl)
Ethyl, 5-phenylpentyl, 5-(3,4-jethoxyphenyl)pentyl, 6-(3,4,5-trimethoxyphenyl)hexyl, 2-methyl-3-(2゜5
-dimethoxyphenyl)propyl group and the like.

Examples of the 5-cyclo lower alkyl group include cyclopropyl, cyclobutyl, cyclopendel, cyclohexyl, cycloheptyl, and cyclooctyl groups.

Lower alkyl groups that may have 3 halogen atoms include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, 1-lyfluoromethyl, 1-heliodomethyl, tribromomethyl, trichloromethyl , 2-trifluoroethyl, 1-
Tribromoethyl, 3-trichloropropyl, 2-tribromoisopropyl, 4-1-lifluorobutyl, 5-
tribromopentyl, rhotrifluorohexyl, 2-
Examples include dibromo-1-chloroethyl, 2-fluoro-1-dichloroethyl, and 4-fluoro-3-difluorobutyl.

Examples of lower alkenyl groups include vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl groups.

Examples of the 6-furyl lower alkyl group include furfuryl, 2-(2
-furyl)ethyl, 1-(3-furyl)ethyl, 3-
(2-furyl)propyl, 4-(2-furyl)butyl,
1.1-dimethyl-2-(2-furyl)ethyl, 5-(
3-furyl)pentyl, 6-(2-noryl)hexyl,
Examples include 2-methyl-3-(3-furyl)propyl group.

Examples of the ditamyl lower alkyl group include 2-chenylmethyl, l-<2-chenyl)ethyl, 1-(2-chenyl)
Ethyl, 3-(3-chenyl)propyl, 4-(2-chenyl)butyl, 1,1-dimethyl-2-(3-chenyl)ethyl, 5-(2-chenyl)pentyl, 6-(2-chenyl)
-thenyl)hexyl, 2-methyl-3-(2-chenyl)propyl, and the like.

Examples of the halogen atom include iodine, bromine, chlorine, and fluorine atoms.

Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.

The derivative represented by the above general formula [1] of the present invention is useful as an anticancer agent '12-(
(N-nitroso)-2-halogenoethylamino)-1,
It is useful as a synthetic intermediate for 3,2-okylyadephosphorinane-2-oxide derivatives.

The method for producing the derivative of the present invention will be described in detail below.

The derivatives of the present invention are produced, for example, by the methods shown in the following reaction schemes -1 and -2.

[Reaction formula-1] [In the formula, R1 is the same as above. ×1 indicates a halogen atom.

] The compounds represented by the general formulas (2) and [3] are known, and the reaction thereof can be carried out in an appropriate solvent in the presence or absence of a basic compound. Any solvent can be used as long as it does not adversely affect the reaction, such as halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride;
Aromatic hydrocarbons such as benzene, toluene, xylene;
diethyl ether, diimpropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
Examples include ethers such as diglyme and triglyme; aliphatic hydrocarbons such as n-hebutane, n-hexane, cyclohexane, and isooctane; and esters such as methyl I acetate and ethyl acetate.

As basic compounds, various compounds that do not adversely affect the reaction, such as triethylamine, tripropylamine,
N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, quinoline, 1゜5-diazabicyclo(4
, 3,0) nonene-5 (DBN), 1,5-diazabicyclo (5,4゜9-O]underene-5 (DBU), 1,4-diazabicyclo (2,2,23 octane (DABCO), etc. Examples include organic bases, and inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.The amount of the compound of general formula [3] to be used for the compound of general formula [2] is not particularly limited and may be within a wide range. The latter can be selected as appropriate from the following, but it is generally preferable to use the latter in an equimolar amount to 3 times the molar amount of the former, preferably in an equimolar amount to 1.5 times the molar amount of the former.

The amount of the basic compound to be used is not particularly limited and may be appropriately selected from a wide range, but it is usually 2 to 5 times the molar amount, preferably 2 to 3 times the molar amount of the compound of general formula [2]. It is better. The reaction temperature is usually -70°C to 100°C,
Preferably the temperature is -10°C to 50°C. Reaction takes 10 minutes
It will be finished in 5 hours.

[Reaction Scheme-2] =10- [In the formula, R', X and x1 are the same as above. ] General formula [1a
] The reaction between the compound of formula [4] (2-halogenoethylamine or a salt thereof) can be carried out in an appropriate solvent in the presence or absence of a basic compound.

The solvents used include various solvents that do not adversely affect the reaction, such as methylene chloride, chloroform, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride, diethyl ether, 1,2-dimethoxyethane, and diglyme. , triglyme, tetrahydrofuran, dioxane and other ethers; benzene, toluene, xylene and other aromatic hydrocarbons; methyl acetate, ethyl acetate and other esters: N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, hexa Examples include aprotic polar solvents such as methylphosphoric triamide.

Examples of the basic compounds used include triethylamine, tripropylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, quinoline,
Examples include organic bases such as DBN, DBU, and DABCO, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. The ratio of the 2-halogenoethylamine of the general formula [4] or its salt to the compound of the general formula [1a] is not particularly limited and can be selected as appropriate, but generally the latter is used in an amount equal to - 5 times the molar amount of the former. , preferably in an equimolar to 3-fold molar amount. The proportion of the basic compound to be used can be generally equimolar to 10 times the molar amount, preferably equimolar to 5 times the molar amount of the compound of general formula (1a).The reaction is generally carried out at -30°C to 1.
The reaction is carried out at 00°C, preferably 0°C to 50°C, for 30 minutes to 30 hours.

The reaction between the compound of general formula [1a] and the aziridine of formula [5] can be carried out in a suitable solvent or in the absence of a solvent, and in the presence or absence of a basic compound. As the solvent and the basic compound, any of the same compounds as those exemplified in the reaction of the compound of general formula [1a] and the compound of general formula [4] can be used. The ratio of the aziridine of formula (5) to the compound of general formula [1a] is generally equivalent to 10 times the molar amount, preferably equimolar to 3 times the molar amount. The proportion of the basic compound to be used is usually equimolar to 5 times the molar amount, preferably equimolar to 3 times the molar amount of the compound of general formula [1a], and the reaction is usually carried out at -50°C to 70°C, 13-10 minutes at a temperature of preferably -30°C to 50°C.
It takes 0 hours to complete.

The subsequent reaction between the compound of general formula [6] and the halogenated hydrocarbon of general formula [7] is carried out after or without isolating the compound of general formula [6] obtained above. . The reaction is carried out in a suitable solvent. As a solvent, various solvents that do not adversely affect the reaction, such as halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride; diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, Examples include ethers such as diglyme, triglyme, tetrahydrofuran, and dioxane; and aromatic hydrocarbons such as benzene, toluene, and xylene.

The usage ratio of halogenated hydrocarbon [a] is according to the general formula [6]
It is usually used in an equimolar to large excess amount, preferably in an equimolar to 5-fold molar amount, relative to the compound.

The reaction is usually carried out at a temperature of -50°C to 50°C, preferably 0°C to around room temperature, for 10 minutes to 5 hours.

14- The target compound obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Incidentally, the present invention naturally also includes optical isomers.

1°3.2- represented by the above general formula (1b) of the present invention
The 2-((N-nitroso)-2-halogenethylamino)-1,3,2-oxazaphosphorinane-2-oxide derivative, which is useful as a cancer control agent, is produced by the method shown in the following reaction scheme-3. This can lead to oxazaphos, a borinane-2-oxide derivative.

[Reaction Scheme-3] [In the formula, R1 and X are the same as above. ] For the nitrosation reaction of the compound represented by the general formula [1b], a wide range of conditions that are used for ordinary N-nitrosation reactions can be adopted. The reaction can be carried out, for example, using a nitrosating agent in the presence of an acid or basic compound in a suitable solvent. Used.

Examples of solvents commonly used in nitrosation reactions include water, lower alcohols such as methanol, ethanol, and isopropanol; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride; acetic acid, etc. Aliphatic carboxylic acids: Aliphatic acid anhydrides such as acetic anhydride; aromatic amines such as pyridine and quinoline. Examples of acids that can be used include mineral acids such as hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid; and organic acids such as acetic acid and formic acid. Examples of the basic compound used include organic bases such as pyridine, quinoline, and sodium acetate, and inorganic bases such as sodium carbonate, potassium carbonate, hydrogen carbonate, and potassium hydrogen carbonate. The nitrosating agents used include alkali metal nitrites such as sodium nitrite and potassium nitrite, and N2O.
3. Nitrogen oxides such as N20L, nitrosyl chloride, etc. can be exemplified. The reaction temperature is usually -60°C to 15°C.
A temperature around 120°C to 7°C can be employed, and the reaction is completed in 5 minutes to 16 hours. The proportion of the nitrosating agent to be used is at least equimolar, preferably equimolar - 8 times the molar amount of the compound of general formula [1b]. The amount of acid or base used is preferably at least an equimolar amount, preferably a large excess amount, relative to the compound of general formula [1b].

EXAMPLES Below, in order to further explain the present invention in detail, an example of WA preparation of the compound 17- of the present invention will be given as an example, and an example of the production of an active ingredient compound of a cancer control agent from the compound of the present invention will be given as a reference example.

Example 1 6.45% of phosphorus oxychloride (] was dissolved in 601% of methylene chloride, and N-(3-hydroxypropyl)- was dissolved under stirring while cooling with water.
A solution of 6.04 liters of aniline and 8.5 g of triethylamine dissolved in 50 ml of methylene chloride was added dropwise, and the reaction was allowed to proceed at the same temperature for 1.5 hours. The methylene chloride was distilled off under reduced pressure to give 2-chloro-3-phenyl-1,
8.3 g of crude crystals of 3,2-oxaazaposborinane-2-oxide were obtained. The crystals were recrystallized from methylene chloride-hexane to obtain 7.8 g of pure colorless needle crystals. Melting point 1
13.5-115℃ Elemental analysis value (Go H+ ICI NO2P and LT)C
〈%) H (%) N (%) Calculated value
46.67 4.79 6.04 Actual value 46
．． 64 4.69 6.0118- Example In the same manner as in Example 1, 8.75Ω of N-(3-hydroxypropyl)-p-1-luidine was treated with oxychloride phosphorus,
980 to form 2-chloro-(3-〇-methylphenyl)-1,3,2-okyly7-the small sulfolinane-2-
Obtain 10 colorless sword crystals of oxide, i+.
.

Melting point 130-132°C6 Elemental analysis value (as CI o H+ 3 CI NO2P) C (%) To1 (%)
N (%) Calculated value 48.89 5.3
3 5.70 Actual value 48.85 5.22
5.69 Example 3 Oxychloride phosphorus, 81+ was dissolved in 100...1 of toluene, and a solution of 12.50 of N-(3-hydroxypropyl)cyclohexane and 210 of triethylamine dissolved in 501 of toluene was added dropwise while stirring under water cooling. The reaction was continued for 1 hour at the same temperature. The reaction mixture was washed successively with 5% hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. 300g of silica gel was added to the residue obtained by distilling off toluene under reduced pressure.
(Chloroform elution) to purify the 2-
A colorless oil of chloro-3-cyclohexyl-1,3,2-oxaazaposborinane-2-oxide 18(+) was obtained, which was identified by IR.

TF? , νmax (neat), cm-'
:2950.2860.1450.1300.124
5.1109.1090.1050゜1015.920
, 820,750 In the same manner as in any of the above examples, the following compounds were obtained using appropriate starting materials.

02-Chloro-3-benzyl-1,3,2-oxaazafosnan-2-oxyde Melting point 69-70.5°C Ethyl acetate-hexane) Colorless needles O2-Chloro-3-(3,4- dimethoxybenzyl)−
1,3,2-Oxaazaphosphorinane-2-oxide NMR 6ppm (CDCI3): 1, 53
~2. 33 (m, 2H)2,. 70-3.
20 (n+, 2l-1)3, 23-3
．． 70 (m, 2 t1) 3, 83 (s,
6H) 4.20-4.76 (111,2 days) 6,70-6.97 (III, 3H) 0
2-chloro-3-cyclopentyl-1,3,2-oxaazaposborinane-2-oxide NMRδppm (
CDC, +3): 1.30-2.43 <m,
10H) 2.87-3.47. (+n, 2H) 3.7
3-4.70 (m, 3H) 02-chloro-3-cyclohebutyl-1,3,2=oxaazaphosphorinane-2-oxide NMRδ11111
111 (CDCI3): 1.13-2.38
(m, 14.H) 2.87-3.92 (m, 3
H) 4.07-4.67 (1,2H) 02-chloro-7-3-cyclooctyl-1,3,2-
Auxazaphosphorinane-2-oxide 21-NMR6DpI (CDCI3): 1,
27-2.33 (m, 16H) 2.9.
0-3.45 (m, 2H)3,. 56-4
．． 03 (m, IH) 4, 13-4.
57 (m, 2'H)02-chloro-3-n
-Butyl-1,3,2-oxaazaphosphorinane-2-
Oxide NMRδDpIII (CDCI 3 ): 066
7-3.57 (+n, 13H) 4.13-4.70
(111,2H)02-chloro-3-n-hexyl-
1,.3.2-Oxaazaphosphorinane-2-oxide NMR6ppm (CDCI3): 0.60~
3.57 (m, 17H) 4.13-4.70 (m
, 2H) 02-Chloro-3-allyl-1,,3,2-oxaazaphosphorinane-2-oxide NMRδ1)l)III (CDCIa): 1
．． 60-2.50 (..., 2H> 2.80-3.53 (n+, 2H) 22-3, 60-4.73 (Ill,
4 t1) 5.03~5. 40 (m,
2H) 5.47-6.03 (m, 1H) 02-Chloro-3-furfuryl-1,3,2-oxa IJ'' Phosphorinane-2-oxide NMR6DI) Il
l (CDCI3): 1.57-2.51 (
+n, 2H) 2°87~3.57 (m, 2H)
3.83-4.67 (m, 4H) 6.23-6.3'7 (m, 2H) 7,33 (t
.
:1, 57 ~2. 43 (Ill, 2
H) 2, 80-3. 50 (m, 2H)
3, 83 to 4, 87 (m, 4H)
6, 80-7.07 (..., 2 days)7,
17-7. 30 (m, 1H)02-Chloro-3-(p-methoxyphenyl)-1,3,2-oxaazaposborinane-2-oxide Melting point = 127-130°C Colorless needle crystals (CH2C12n-hexane) 02 -Chloro-3-(p-fluorophenyl)-1,3,2-oxaazaposborinane-2-oxide Melting point: 132-134°C Colorless prismatic crystals (0 days 2Cl, 'n-hexane) 02- Chloro-3-(m-t-lifluoromethylphenyl)-1,3,2-oxaazaphosphorinane-2-oxide NMRδFIpIII (CDCI 3): 1.6
7-2.67 (m, 21-1>3, 00-4.
00 (m, 21-1>4.20~4.80
(m, 2l-1)7.23~7.67 (+n
, 4H) 02-chloro-3-(3,4-dichlorophenyl)-1,3,2-oxaazaposborinane-2-oxide Melting point: 114-116°C Pale yellow plate crystals (CH2CI 2-n-h) *")"hmm)
Example 4 2-chloro-3-phenyl-1,3,2-oxaazaphosphorinane-2-oxide4. '63 (l) and 2.99 ml of 2-chloroethylamine hydrochloride were stirred in 50 ml of methylene chloride under ice-cooling, and a solution of 5.1 g of triethylamine dissolved in 30 ml of methylene chloride was added dropwise, followed by stirring at room temperature for 20 hours. Reaction. The mixture was washed successively with 5% hydrochloric acid and water, and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and 2
-(2-chloroethylamino)-3-phenyl-1,3
4.9 g of crude crystals of 2-oxazaphosphorinane-2-oxide were obtained. The crystals were recrystallized from ethyl acetate to obtain pure colorless needle crystals of 4.5Ω.

Melting point: 113-115℃ Elemental analysis value (C'+ + Hla N2'02 PC
As I) 25- C (%) H (%) N (%) Calculated value
4.8.10 5.87 10.20 Actual value 4.
7.98 5.74 10.31 Example 5 2-chloro-3-(p-methoxyphenyl)-1,3,
2-Oxaazaphosphorinane-2-oxide 5.25 (
A solution of 1 g of aziridine dissolved in 10 ml of methylene chloride was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. Next, while stirring under water cooling, excess dry hydrogen chloride gas was added, and the mixture was heated to the same temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-(2-chloroethylamino)-3-
6 g of crude crystals of (p-methoxyphenyl)-1,3,2-oxaazaposborinane-2-oxide were obtained. The crystals were recrystallized from ethyl acetate to obtain 5.7 g of pure colorless needle crystals.

Melting point: 123-124°C Elemental analysis value (as CI'2 Hla N2O3PC'1) 26- C (%) H (%) N (%) Calculated value 47.30 5.95 9.19 Actual value 4
7.34 5.85 9.25 Example 6 4.99 of 2-chloro-3-benzyl-1,3,2-oxaazaphosphorinane-2-oxide and 2.60 of β-chloroethylamine hydrochloride The mixture was stirred in 60 ml of methylene chloride under ice cooling, and a solution of 4.5 g of triethylamine dissolved in 20 ml of methylene chloride was added dropwise, followed by stirring at room temperature for 20 hours. The reaction mixture was washed successively with 5% hydrochloric acid, water, and saturated brine, and dried over anhydrous magnesium sulfate. Methylene chloride was distilled off under reduced pressure to obtain 5.6 g of crude crystals of 2-(2-chloroethylamino)-3-benzyl-1,3,2-oxaazaposborinane-2-oxide.

The crystals were recrystallized from ethyl acetate-ether to obtain 5.3 g of pure colorless needle crystals.

Melting point = 90~92℃ Elemental analysis value (as C+ 2H+ a N202 Pct) C (%) H (%) N (%) Calculated value 4
9.92 6.28 9.70 Actual value 49.8
8 6.13 9.75 The following compounds were obtained in a similar manner to either Example 4.5 or 6 using appropriate starting materials.

02-(2-chloroethylamino)-3-cyclohexyl-1,3,2-okinaazaphosphorinane-2-oxide Melting point: 102-103.5°C Colorless needles (ethyl acetate) 02- (2-chloroethylamino)-3-(3゜4-dimethoxybenzyl)-1,3,2-oxaazaposborinane-2-oxide Melting point: 111-113°C Colorless needle crystals (ether-〇-hexane) )02-(2-chloroethylamine)-3-cyclopentyl 1.3.
2-Oxaazaphosphorinane-2-oxide Melting point: 100-102°C Colorless needle crystals (ethyl acetate) 02-(2-chloroethylamino)-3-cyclohebutyl-1,3,2-oxazaphosphorinane Nan-2-oxide melting point 2 95-96°C Colorless needle crystals (n-hexane-ether) 02-(2-chloroethylamino)-3-cyclooctyl-1,3,2
-Oxaazaphosphorinane-2-oxide Melting point: 80-81°C Colorless needle crystals (n-hexane-ether) 02-(2-chloroethylamino)-3-n-butyl-1,3,2-oxa Azafosborinane-2-oxide NMRδDDm (CDCI 3): 0.73-2
．． 07 (1,9H) 2.53-3.67 (m, 9H) 3.87-4.53 (m, 21-(>02-(2
-chloroethylamino)-3-n-hexyl-1,3,
2-Oxaazaphosphorinane = 2-oxide 29- NMR δ11+1111 (CDCI3)
:0.67~2.03 (m, 13H)2.5
3-4.43 (m, 11H)02-(2-chloroethylamino)-3-allyl-1,3,2-oxaazaposborinane-2-oxide NMR6ppn+ (CDCI3): 1.60
~2.50 (m, 2H) 2.80-4.73 (m, 11H) 6.03-5.
40 (m, 2H) 5.47-6.03 (m, IH) 02-(2-chloroethylamino)-3-furfuryl-
1,3,2-oxaazaphosphoritin-2-oxide NMR6FIF1m (CDCI 3): 1.60
~2.10 (m, 2H>2.80-4.67 (m, 11H) 6.03-6.
30 <m, 2H) 7.17-7.3.0 (i+, IH)02-(
2-Chloroethylamino)-3-(2-30-thenylmethyl)-1,3,2-oxaazafosborinane-2-oxide Melting point: 108-109.5°C Colorless cylindrical crystals (ethyl acetate-n- hexane)02-(2-
chloroethylamino)-3-(p-methylphenyl)
-1,3,2-Oxaazaphosphorinane-2-oxide Melting point: 104-106°C Colorless needles (ethyl acetate) 02-(2-chloroethylamino) -3-(p-fluorophenyl)-1 ,3,2-oxaazaposborinane-2-oxide Melting point 284-85°C Colorless needles (ethyl acetate) 02-(2-chloroethylamino)-3-(i-trifluoromethylphenyl)-1 ,3,2-Oxaazaphosphorinane-2-oxide Melting point 2 89-91℃ Colorless needle crystals (ethyl acetate-〇-hexane) 02-(2-
Chloroethylamino)-3-(3゜4-dichlorophenyl)-1,3,2-oxaazaposborinane-2-oxide Melting point = 101-103°C Colorless needle crystals (methylene chloride-〇-hexane) Reference example 1 2-(110loethylamino)-3-phenyl-1,
3,2-Ogisaazabosfolinan-2-oxide 1.3
1 g of the solution was dissolved in 13 ml of 90% formic acid, and a solution of 1 g of sodium nitrite dissolved in 10 ml of water was added dropwise to the Nakatsu salt-ice bath at an internal temperature of -10°C to 0°C, followed by stirring at the same temperature for 10 minutes. The reaction solution was added to 50 ml of ether, washed successively with water, saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. The ether was distilled off under reduced pressure below room temperature, and the residue was crystallized from ether-hexane to give 2-((N-nitroso)-2-chloroethylaminoco-3-phenyl-1,3゜2-oxane. Pale yellow crystals of azaphosborinane-2-oxide 1,2Q were obtained.The crystals were recrystallized from ether-hexane to obtain 1 g of pure pale yellow prismatic crystals.

Melting point: 47-48℃ (decomposition) IRvmay, (KBI'): 1600
, 1 480. 1 280, 1180.10110
1O' Elemental analysis value (C+ + H+ 5 CI N303P) C (%) H (%) N (%) Calculated value 43
．． 51 4.98 13.84 Actual value 43.32
4.9i 13.81 Reference Example 2 2-(2-chloroethylamino)-3-benzyl-1,
3,2-Oxaazaphosphorinane-2-oxide 1.1
6o was dissolved in 90% formic acid 121, and while cooling and stirring in a saline bath, a solution of sodium nitrite 8301 () dissolved in 101 water was added dropwise, and the mixture was stirred at the same temperature for 10 minutes. 50 ml of ether was added to the reaction mixture, The mixture was washed successively with cold water, a cold saturated aqueous sodium bicarbonate solution, and cold water, and dried over anhydrous sodium sulfate.The ether was distilled off under reduced pressure at room temperature or below, and the 33-residue was crystallized from ether-hexane to give 2- ((N
950n+o of pale yellow crystals of -nitroso)-2-chloroethylaminoco-3-benzyl-1,3,2-oxaazaphosphorinane-2-oxide were obtained.

Melting point = 53-54℃ (decomposition) (that's all) 34-

Claims (1)

[Claims] ■ General formula (in the formula, R1 is a phenyl group that may have 1 to 3 groups selected from lower alkyl groups, lower alkoxy groups, and halogen atoms as substituents on the phenyl ring, phenyl A phenyl lower alkyl group that may have 1 to 3 lower alkoxy groups on the ring, a cyclo lower alkyl group, a lower alkyl group that may have 3 halogen atoms, a lower alkenyl group, a furyl lower alkyl group, or a chenyl lower alkyl group. R2 represents a halogen atom or a NHCH2CH2X (X represents a halogen atom) group. However, when R2 is a halogen atom, R1 represents a lower alkoxy group on the phenyl ring.
It must not be an α-phenyl lower alkyl group, which may have three groups. ] 1,3,2-oxaazaposborinane-2 represented by
-Oxide derivatives.